Kinetics and mechanism of uptake of platinum-based pharmaceuticals by the rat small intestine.

The absorption of two platinum-based pharmaceuticals, cisplatin and carboplatin, was studied using in vitro and in situ models. By utilizing everted rat small intestine, it was found that absorption of both drugs was linear with time up to 60 min and was not saturable up to a concentration of 1.0 mM. Moreover, uptake against a concentration gradient could not be demonstrated and absorption was not reduced by metabolic inhibition or anoxic conditions. These results indicate the lack of involvement of an active transport mechanism for cisplatin and carboplatin and imply that absorption across the gastrointestinal tract is by passive diffusion. Cisplatin was absorbed more readily than carboplatin, both in vitro and in situ. In situ both drugs were found to disappear from the intestinal lumen following first-order kinetics. The results of in situ studies indicate that a decrease in pH of the perfusion medium leads to an increase in absorption of carboplatin into the systemic blood. This report establishes the fact that both cisplatin and carboplatin are absorbed across the gastro-intestinal tract and indicates that preclinical trials involving oral administration of platinum-based pharmaceuticals could be justified.

Hexavalent chromium produces DNA strand breakage but not unscheduled DNA synthesis at sub-cytotoxic concentrations in hepatocytes.

Rat hepatocytes were used to investigate the possible induction of unscheduled DNA synthesis (UDS) and the extent of DNA strand breaks induced by sodium dichromate (a representative chromium(VI) compound) and chromium acetate hydroxide (chromium(III)) in vitro. Cytotoxicity, measured using tetrazolium salt (MTT) reduction assay, was found at a much higher dose of chromium(III), (> 50 microM), compared to that of chromium(VI), (> 2.5 microM), in cultured hepatocytes over 20 h treatment at 37 degrees C. Chromium(VI), but not chromium(III), stimulated minimal UDS in hepatocytes at sub-cytotoxic concentrations. A positive UDS response was only observed at cytotoxic concentration. DNA strand breaks in hepatocytes were induced by chromium(VI) following incubation at 37 degrees C for 1 h at doses of 10, 20 and 40 microM sodium dichromate. The subsequent ligation of such strand breaks in hepatocytes treated with 40 microM chromium(VI) for 1 h at 37 degrees C was demonstrated. The majority of strand breaks was repaired within 30 min following removal of the chromate. In conclusion, chromate-induced DNA strand breakage, possibly involving the formation of oxygen radicals and lack of significant UDS have some analogy to those produced by ionizing radiation.

Induction of DNA strand breaks in peripheral lymphocytes by soluble chromium compounds.

1. Incubation of human lymphocytes with sodium dichromate (CrVI) at 37 degrees C for 3 h resulted in a dose-dependent increase in DNA strand breaks without concurrent cytotoxicity. In contrast, chromium acetate hydroxide (CrIII) failed to induce DNA strand breaks at sub-cytotoxic concentrations. 2. DNA strand breaks were also detected in the peripheral lymphocytes of Wistar rats, 24 h after intratracheal instillation of sodium dichromate (1.3 and 2.5 mg kg-1). Instillation of chromium acetate hydroxide (up to 21.8 mg kg-1) failed to induce DNA strand breaks in peripheral lymphocytes. In accord with previous studies, hexavalent chromium was found to be more readily absorbed from the lungs into the peripheral blood than chromium in its trivalent form. 3. The results of this study indicate that fluorometric analysis of DNA unwinding (FADU) in peripheral lymphocytes might be a convenient method of measuring an important biological effect of chromium in occupationally-exposed workers.

Occupational toxicology and the control of exposure to pharmaceutical agents at work.

BACKGROUND: The pharmaceutical industry employs >350 000 people worldwide in operations including research and development (R&D), manufacturing, sales and marketing. Workers employed in R&D and manufacturing sectors are potentially exposed to drug substances in the workplace that are designed to modify physiology and also to chemical precursors that are potentially hazardous to health. Pharmaceutical workers are at risk from adverse health effects, including occupational asthma, pharmacological effects, adverse reproductive outcomes and dermatitis. AIM: This study aimed to describe the approaches taken by pharmaceutical companies for identifying and communicating potential adverse health effects that may result from workplace exposures and in setting 'in-house' exposure control limits and to highlight the challenges in controlling workplace exposures to increasingly potent compounds. METHOD: The literature was reviewed by searching the Medline and HSELine databases. RESULTS: The findings are presented in five sections, covering: test methods and approaches to occupational toxicology; hazard communication; approaches to setting health-based occupational exposure limits for pharmaceutically active agents; recent approaches to risk control; and occupational hygiene and exposure controls. CONCLUSION: Significant efforts have been directed at predicting and evaluating potential occupational health hazards in the pharmaceutical industry. The pharmaceutical industry has provided leadership in controlling exposure to hazardous substances. Much of this work has been driven by a real need to control occupational exposures to substances that can have profound adverse health effects in exposed employees and that are becoming increasingly more potent.

Establishing guidance for the handling and containment of new chemical entities and chemical intermediates in the pharmaceutical industry.

This information is intended to guide scientists and technicians working with pharmaceutical substances early in development, before occupational exposure levels (OELs) can be set. The focus is on determining hazard categories, or occupational exposure bands, which may be applied temporarily until full health-based OEL's are in place.